Virological outcome of chronic hepatitis B virus infection in HIV-coinfected patients receiving anti-HBV active antiretroviral therapy.

The immune suppression caused by HIV infection accelerates the course of liver disease caused by chronic hepatitis B virus (HBV) infection. We assessed the outcome of HIV/HBV-coinfected patients exposed to highly active antiretroviral therapy (HAART) including anti-HBV active drugs. Baseline and follow-up plasma HBVDNA and HIV-RNA levels, HBV serological markers, and CD4 counts were longitudinally evaluated in all HBsAg(+) individuals with HIV infection on regular follow-up at an urban HIV reference clinic. Out of 79 HBsAg(+) chronic carriers identified, 39 (50%) were HBeAg(+). Lamivudine (3TC) alone had been received by 37% of patients, while 3TC plus tenofovir (concomitantly or consecutively) had been taken by 58% of them. The median follow-up was of 52 months. Loss of HBeAg or HBsAg occurred in 28% (10/36) and 13% (10/75) of patients, respectively. In multivariate analysis, only undetectable plasma HIV-RNA levels [OR 4.58 (95% CI 1.25-16.78); p = 0.02] and greater CD4 gains on HAART [OR 1.003 (95% CI 1.000-1.006); p = 0.03] were associated with undetectable serum HBV-DNA at the end of follow-up. Anti-HBV active HAART makes it possible to achieve HBsAg clearance, anti-HBe seroconversion, and suppression of HBV replication in a substantial proportion of HBV/HIV-coinfected patients, particularly in those with complete HIV suppression and greater immune recovery. Thus, HBV/HIV-coinfected patients might benefit from an earlier introduction of HAART.

Selection of hepatitis B virus polymerase mutations in HIV-coinfected patients treated with tenofovir.

BACKGROUND: Tenofovir (TDF) is an adenosine nucleotide analogue that has been approved for the treatment of HIV-1 infection. It also shows activity against hepatitis B virus (HBV) in patients with or without lamivudine (LAM)-associated mutations. Development of clinical or virological HBV breakthrough during TDF therapy has not been reported so far. The aim of this study was to analyse the HBV polymerase (pol) from HIV/HBV-coinfected patients with detectable serum levels of HBV DNA during treatment with TDF for longer than 6 months. METHODS: The HBV pol was sequenced from 43 patient's serum before and during TDF therapy. Phenotypic analyses were performed using HBV replication-competent plasmids carrying unique mutations selected under TDF therapy. RESULTS: Mean exposure to LAM was 35.3 +/- 27.5 months and to TDF 11.2 +/- 6.7 months. Genotypic analyses from 21 of the patients revealed LAM-associated mutations, and a further two patients developed a novel mutation, rtA194T, along with LAM-resistance-associated mutations. Phenotypic analyses revealed that constructs harbouring rtA194T combined with rtL180M and rtM204V displayed an over 10-fold increase in the IC50 for TDF compared with the wild type. CONCLUSION: The selection of HBV mutations in HBV/HIV-coinfected patients failing TDF therapy is an unlikely event within the first 12 months of treatment. However, HBV from two of the 43 patients treated with TDF for more than 12 months was found to contain one novel mutation located distal to the catalytic site of the HBV pol. In vitro, rtA194T conferred a reduced susceptibility to TDF in the presence of LAM-associated mutations.

Impact of ribavirin exposure on early virological response to hepatitis C therapy in HIV-infected patients with chronic hepatitis C.

BACKGROUND: The use of pegylated interferon (PEG-IFN) plus ribavirin (RBV) is currently the recommended treatment for chronic hepatitis C virus (HCV) infection. Coinfection with HIV is a negative predictor of response, for reasons not well understood. METHODS: We examined the virological response at weeks 4 and 12 in 198 HCV/HIV-coinfected patients enrolled in a prospective trial in which PEG-IFN alpha 2a (180 microg per week) and RBV (1000-1200 mg daily) were provided. RESULTS: In an on-treatment analysis, 52.8% of patients achieved undetectable HCV-RNA (<600 IU/ml) at week 4, while 63% and 77.2% of patients had a decline of at least 2 and 1 log10, respectively. At week 12, 73.1% of patients reached undetectable HCV-RNA, and 83.5% and 89% achieved at least a 2- and 1-log10 drop, respectively. More than 85% of HCV genotypes 2/3 cleared HCV-RNA at week 4, a proportion significantly higher when compared with genotypes 1 (33.8%) and 4 (28.6%). Multivariate logistic regression analysis identified genotype 3 and RBV exposure (mg/kg of body weight) as independent predictors of virological response at week 12 of therapy. CONCLUSION: Early virological response rates to PEG-IFN plus RBV in HCV/HIV-coinfected patients seem to be similar to those reported for HCV-monoinfected subjects. The use of suboptimal doses of RBV in most earlier trials might account for the low response rates seen in coinfected patients. To our knowledge, this is the first report demonstrating that RBV exerts a significant independent effect on early virological response. Therefore, strategies aimed at optimizing doses and adherence to RBV might help to improve responses to HCV therapy in coinfected patients.

Hepatitis C viremia in HIV/HCV-coinfected patients: lower levels in presence of chronic hepatitis B.

Complex reciprocal interactions between hepatitis C (HCV) and hepatitis B (HBV) viruses (HBV) have been reported. We examined the influence of HBV on HCV RNA titers in 376 HCV/HIV-coinfected patients (30 were also HBsAg positive). Regression analyses identified negative HBsAg and male sex as factors associated with HCV RNA values >500,000 IU/mL.

C-reactive protein levels and prevalence of chronic infections in subjects with hypoalphalipoproteinemia.

Low levels of high-density lipoprotein cholesterol (HDL-C) show a consistent relationship with the development of atherosclerosis. The underlying mechanisms are not well understood, but recent studies in subjects with primary hypoalphalipoproteinemia suggest that this could represent a proinflammatory condition. To better assess the link between HDL-C levels and C-reactive protein levels and the possible role of chronic infections as putative mediators of this relationship, we studied a population sample with nonselected causes of hypoalphalipoproteinemia. Eighty-six consecutive patients with HDL-C levels below 40 mg/dL who attend our lipid clinic and 86 control subjects with normal concentrations matched for gender, age, smoking habit, and weight were included in the study. Mean HDL-C levels were 34 +/- 3.9 and 55.4 +/- 8.8 mg/dL for subjects with hypoalphalipoproteinemia and control subjects, respectively. C-reactive protein concentrations were increased in case patients as compared with control subjects (2.13 +/- 2.0 vs 1.52 +/- 1.8 mg/L; P = .025). The prevalence of herpes simplex virus type 1, cytomegalovirus, Chlamydia pneumoniae , and Helicobacter pylori infections did not differ between the 2 groups. Although a possible confounding variable could be a degree of insulin resistance within the group of patients with low HDL-C levels, our results indicate that C-reactive protein levels are increased in subjects with nonselected hypoalphalipoproteinemia and that chronic infections do not appear to mediate this relationship.

Hepatitis C virus-RNA clearance in HIV-coinfected patients with chronic hepatitis C treated with pegylated interferon plus ribavirin.

Hepatitis C virus (HCV)-RNA clearance seems to occur more slowly in HIV/HCV-coinfected patients than in HCV-monoinfected subjects treated with pegylated interferon alpha (peg-IFN) plus ribavirin (RBV). As a consequence, concern has arisen over the feasibility of following the treatment rules applied to HIV-negative patients with chronic hepatitis C. A total of 89 HIV/HCV-coinfected patients who had fully completed a course of peg-IFN plus RBV were analysed. Of these, 29 (32.6%) reached sustained virological response (SVR). Reductions >2 logs in plasma HCV-RNA occurred in 52 (58%) patients at week 12 of treatment (early virological response; EVR). None of patients who showed HCV-RNA drops <2 logs at week 12 reached SVR (negative predictive value: 100%). The positive predictive value of EVR was 56%. On the other hand, relapses occurred in 19 (39.6%) out of the 48 patients who had negative HCV-RNA at the end of treatment, and there were no differences noted when comparing patients with HCV genotypes 2/3 and 1/4. In summary, the quantitative assessment of plasma HCV-RNA at week 12 predicts the chance of SVR using peg-IFN plus RBV in HIV-positive patients with chronic hepatitis C, as it does in HIV-negative individuals. Thus, discontinuation of anti-HCV therapy, which is associated with frequent side effects, might be warranted in HIV/HCV-coinfected patients showing HCV-RNA reductions <2 logs at week 12 of treatment. On the other hand, relapses in virological responders were unexpectedly high in HIV/HCV-coinfected patients when treatment was provided following the rules applied to HIV-negative subjects. This is particularly relevant for HCV genotypes 2/3, which only rarely relapse in HIV-negative patients. Therefore, extending therapy (for 12 months in HCV genotypes 2/3 and perhaps for 18 months in HCV genotypes 1/4) might be warranted in HIV/HCV-coinfected patients showing EVR.

Neumonía por Bordetella bronchiseptica en pacientes con infección por el VIH / Bordetella bronchiseptica pneumonia in patients with HIV

No disponible

Different viral rebound following discontinuation of antiretroviral therapy in cases of infection with viruses carrying L74V or thymidine-associated mutations.

A total of 76 patients discontinued treatment with didanosine plus hydroxyurea after 1 year of maintenance therapy. The greatest human immunodeficiency virus (HIV)-RNA rebounds were seen in 10 patients harboring an L74V mutation, and the presence of viruses with this mutation rapidly waned. In contrast, viral rebounds were significantly less pronounced (P < 0.01) in 12 subjects harboring thymidine-associated mutations; these mutations persisted in all instances. Thus, selection of an L74V mutation during didanosine therapy may compromise HIV replication in vivo.

Treatment of chronic hepatitis B in the human immunodeficiency virus-infected patient: present and future.

The management of chronic hepatitis B poses specific problems in the presence of human immunodeficiency virus (HIV) coinfection, because therapeutic approaches have to address both hepatitis B virus (HBV) and HIV infections. Response to interferon (IFN-alpha) is lower in HBV-HIV-coinfected than in HIV-negative subjects, especially in patients in advanced stages of immunosuppression. Thus far, there are no data on the performance of the new pegylated forms of IFN-alpha in HBV- and HIV-coinfected persons. After prolonged use of lamivudine, resistance develops in the majority of HBV-HIV-coinfected patients treated with the drug. The more recently approved tenofovir has shown excellent short-term results, and data from longer follow-up studies are eagerly awaited. Several drugs with combined anti-HIV and anti-HBV activity have recently been approved (emtricitabine) or are currently under development. Preliminary results with some of them are quite promising and probably will widen the therapeutic armamentarium against hepatitis B in patients with HIV infection.

Hydroxyurea plus didanosine as maintenance therapy for HIV-infected patients on long-term successful highly active antiretroviral therapy.

BACKGROUND: Toxicity and quality of life issues have moved to delay the initiation of highly active antiretroviral therapy (HAART) and to explore novel treatment strategies for HIV infection. The switch to simpler regimens or treatment discontinuation has been attempted with limited success. The combination of hydroxyurea (HU) plus didanosine (ddI) is a simple regimen that might be able to restrain virus replication for long periods of time and could be an acceptable option as maintenance therapy in patients on prolonged successful HAART. METHOD: The combination of HU (500 mg bid) plus ddI (400 mg qd) was offered to participants with viral load (VL) <50 HIV RNA copies/mL and CD4 counts >350 cells/microL for more than 6 months under HAART. The prior HAART regimen was resumed if VL rose to >5,000 copies/mL and/or the CD4 count fell to <200 cells/microL after being on HU + ddI maintenance therapy. RESULTS: A total of 187 participants replaced HAART with HU + ddI. In an intent-to-treat analysis at 48 weeks, 109 (58%) and 77 (41%) patients had VL below 5,000 and 500 HIV RNA copies/mL, respectively. The mean CD4 count dropped from 809 +/- 283 to 573 +/- 270 cells/microL, while 77% of patients remained above 350 cells/microL. The proportion of participants with hypercholesterolemia declined from 70% to 46% (p <.001), while those with hypertriglyceridemia fell from 36% to 21% (p <.05). Significant improvements in lipohypertrophy and lipoatrophy were observed in 52% and 64% of participants, respectively. Grade 3-4 toxicities appeared in 20 patients (11%), including 3 cases of pancreatitis and 1 of peripheral neuropathy. Prior history of VL >5 log, CD4 counts <200 cells/microL, and ddI experience were independently associated with lower response to HU + ddI maintenance therapy. CONCLUSION: The combination of HU + ddI may be a satisfactory maintenance therapy for more than half of patients on successful HAART who want to alleviate drug-related toxicities and/or pill burden. Patients with metabolic and/or body-shape abnormalities might particularly benefit from switching to this simple regimen.

Replacement of protease inhibitors by nevirapine or efavirenz in simplification and rescue interventions: which works better?

The outcome of 162 patients replacing protease inhibitors (PIs) by nonnucleoside reverse transcriptase inhibitors (NNRTIs) was retrospectively assessed. After 48 weeks of follow-up, nevirapine (NVP) and efavirenz (EFV) performed similarly well in simplification interventions in patients with undetectable viremia, while EFV provided significantly better results in rescue interventions after PI failure. Previous suboptimal exposure to nucleoside analogs conditioned lower chances of virologic success using either NVP or EFV. Both drugs were generally well tolerated, although specific toxicities could make one drug more suitable than the other for certain patients.

Comparison of the efficacy, safety and predictive value of HIV genotyping using distinct ritonavir-boosted protease inhibitors.

The pharmacokinetic profile of protease inhibitors (PI) is improved significantly by adding low doses of ritonavir (rit). The use of rit-boosted PI allows the reduction of pill burden, improves dosing schedules and enhances drug exposure, all factors that have been associated with a greater benefit of antiretroviral therapy. All patients receiving rit 100 mg bid together with saquinavir (SQV) soft gel 1000 mg bid, indinavir (IDV) 800 mg bid or lopinavir (LPV) 400 mg bid, as part of a salvage regimen, were retrospectively analyzed in a reference institution. Only subjects who had failed all three antiretroviral drug families in the past were included. A total of 299 patients were included in the study (121 on SQV, 62 on IDV and 116 on LPV). Mean plasma HIV-RNA and CD4 lymphocyte counts at baseline were less favourable in the LPV group (4.4 logs, 275 cells/microl) with respect to SQV (4.3 logs, 355 cells/microl) and IDV (3.7 logs, 409 cells/microl) groups (P < 0.05). The proportion of subjects experiencing virological success (attainment of either < 500 HIV-RNA copies/ml or > 1 log reduction) in an intent-to-treat analysis at 24 weeks was 61% with LPV, 49% with SQV and 48% with IDV. The CD4 count increased 48% with SQV, 45% with IDV and 37% with LPV. The proportion of subjects discontinuing therapy due to adverse events was higher using IDV (27%) than using either SQV (11%) or LPV (6%) (P < 0.05). The presence of < 5 or > 5 PI resistance mutations at baseline discriminated significantly better who would respond to therapy in all instances: 90 vs. 48% with LPV, 95 vs. 21% with SQV and 90 vs. 23% with IDV. The efficacy of rit-boosted PI combinations is greatly influenced by the extent of baseline PI resistance. Differences, not only in potency, but mainly in tolerance may favour the selection of one dual PI combination over others.